PDD 10 and 11: Capsules Flashcards
What are capsules?
solid dosage form in which one or more medicinal and/or inert substances are enclosed within a small shell, usually prepared from gelatin (blends of type A and B)
What are the 2 types of capsules?
- hard gelatin capsules
- soft gelatin capsules
What are hard gelatin capsules?
- two sections, one slipping over the other to completely surround the formulation
- used mostly for powders or granules
What are soft gelatin capsules?
- made from a more flexible, plasticized gelatin film than hard gelatin capsules
- used mostly for liquids, semi-solids, oily substances
What are the advantages of hard gelatin capsules vs. tablets? (8)
- patients find them easier to swallow
- tasteless
- easier to manufacture
- powder-filled hard capsules allow more flexibility in dosing (important for community or hospital pharmacist)
- allowing filling of various combinations of diverse systems
- fast disintegration within GI tract (also a disadvantage)
- very convenient for preliminary drug studies (phase 1), including for blinded studies
- easy to make identifiable
What are the disadvantages of hard gelatin capsules vs. tablets? (2)
- overall production is slower
- fast disintegration within GI tract (esophageal or gastric irritation, highly potent compounds) – also an advantage
Plasma Concentration vs. Time Graph
Capsules vs. Tablets
- capsules: plasma concentration increases quicker
- tablets: plasma concentration increases slower
Describe the sizes of hard gelatin capsules.
- empty capsules are manufactured in various sizes
- for humans, sizes range from 000 (largest) to 5 (smallest)
- pharmacist will have to determine the size of capsule for a given prescription
What are the shell components of hard capsules? (5)
- gelatin (or starch, hydroxypropylmethylcellulose)
- colorants
- opaquing agents (titanium dioxide)
- preservatives (ie. parabens)
- 15-18% water (30-40% initially)
What is gelatin?
mixture of peptides and proteins of partially hydrolyzed collagen
What is the purpose of colorants?
for identification and compliance
How is pharmaceutical-grade gelatin produced?
using collagen derived from mammals (beef bones)
- collagen is hydrolyzed and heat-denatured, breaking apart cross-linking between adjacent triple-helices and bonds within peptide chains
What is gelatin powder?
heterogeneous mixture of proteins and peptides
Describe the characteristics of pharmaceutical-grade gelatin.
improved aqueous solubility
- insoluble in cold water (a semi-solid hydrocolloid gel forms)
- soluble in gastric fluid, warm water, most polar solvents
What are the steps of manufacturing hard capsules?
- powder preparation
- capsule (shell) preparation
- capsule filling
- capsule locking and sealing
- capsule finishing (cleaning, polishing)
- quality control – accept or reject
Hard Capsule Powder Preparation
How is proper fill volume achieved?
by adding fillers and milling powders
- ie. lactose, microcrystalline cellulose, starch
Hard Capsule Powder Preparation
How is proper disintegration of contents achieved?
by adding disintegrants
- ie. pregelatinized starch, croscarmellose, sodium starch glycolate
Hard Capsule Powder Preparation
How are free flowing contents (when caps are being filled) achieved?
by lubricants/glidants
- ie. fumed silicon dioxide, stearic acid, talc
Hard Capsule Powder Preparation
What is used for proper wetting?
surface active agent
- ie. Na+ lauryl SO4
Can aqueous liquids be put in hard gelatin capsules?
no – due to risk of leakage
Can semi-solids (like pastes) be put in hard gelatin capsules?
OK if the liquid component is not aqueous
Hard Capsule Shell Production
How are shells produced?
- dipping of pins into a reservoir of melted gelatin mixture (includes excipients)
- pins are lifted and rotated
- gelatin is dried by gentle air flow that is temperature and humidity-controlled
- bronze jaws strip the body and cap from pins
- body and cap are transferred into collets in which they are firmly held
- collet rotates and a knife trims the capsule piece to the desired length
Hard Capsule Filling
- compatibility with gelatin
- automatic machines – fine particles are better
Hard Capsule Filling
Describe manual filling.
- mixing the ingredients, reducing to a fine powder (granules do not pack readily in capsules)
- potent drugs given in small doses usually are mixed with an inert diluent (lactose)
- the powder is usually placed on paper and flattened with spatula to about 1/3 of capsule length
- the cap is removed and the body is pressed repeatedly into the powder until it is filled
- the spatula is useful in pushing the last quantity of powder into the capsule
- the cap is replaced and the capsule is weighed
Hard Capsule Filling
Describe extemporaneous manual filling machines.
- entire capsules are placed in the machine by hand or using different devices
- drug is swiped into the capsules
- the lower plate carries a clamp which holds the capsule bases and makes it possible to remove and replace the caps
Hard Capsule Filling
Describe semi-automatic filling machines.
- same principle – separation of cap from body, filling the body half and rejoining the cap and body halves
- powders frequently include diluents (lactose, mannitol) and lubricants (stearate)
Hard Capsule Filling
Describe automatic filling machines.
- same principle, larger quantities – separation of cap from body, filling the body half and rejoining the cap and body halves
- main difference between machines is how the formulation is dosed into the capsules
- one operator can handle more than one machine
Hard Capsule Locking
What is positive closure?
sealing and locking
- helps prevent the separation of capsules during shipping and handling
Hard Capsule Locking
Describe the capsule locking.
hard-gelatin capsules are made self-locking by forming indentations or grooves on the inside of the cap
- tapered rim avoids telescoping
- indentations prevent premature opening
- grooves lock the two halves together once the capsule has been filled
Hard Capsule Sealing
What are the 2 ways that hard gelatin capsules are hermetically (air-tight) sealed?
- extemporaneously
- in manufacturing
Hard Capsule Sealing
What is extemporaneous sealing?
water and a cotton swab
Hard Capsule Sealing
What are the 2 types of sealing in manufacturing?
- banding
- microspray sealling
Hard Capsule Sealing
What is banding?
polymer or gelatin (often distinctively colored) band around the seam
- currently is the single most frequently used sealing method)
Hard Capsule Sealing
What is microspray sealing
water and ethanol are sprayed around the seam area, followed by thermal bonding
Hard Capsule Cleaning
- all capsules, whether they have been filled by hand or machine, will require cleaning
- hand polishing with a cloth or gauze in a case of a small batch
- for large quantities, rotation or shaking with crystalline sodium chloride
- capsules are then rolled on a cloth-covered surface
Hard Capsule Finished Product Testing
- weight – batch testing
- appearance
- visual or electronic monitoring
- high reject rate → evaluate process
- fillling into containers and labeling is automated in manufacturing, and these steps are also subject to the requirements of Good Manufacturing Practice (GMP)
Describe soft gelatin capsules.
soft, globular, gelatin shell that is somewhat thicker than hard gelatin capsules
What is generally needed for the preparation and filling of soft gelatin capsules?
large scale production
What shapes are soft gelatin capsules?
commercially filled soft gelatin capsules come in a wide choice of sizes and shapes
- round
- oval
- oblong
- tube or suppository-shaped
How do soft gelatin capsule shells compare to hard gelatin capsule shells?
basic component is also gelatin, however, the shell has been plasticized by the addition of glycerin/glycerol or sorbitol (or both)
What determines the ‘hardness’ of soft gelatin capsules?
ratio of dry plasticizer to dry gelatin
- the larger the number, the softer the capsule
Soft Gelatin Capsules
What are lower ratios (0.3-0.5) of dry plasticizer to dry gelatin used for?
oily vehicles
Soft Gelatin Capsules
What are intermediate ratios (0.4-0.6) of dry plasticizer to dry gelatin used for?
oily vehicles that include surfactant
Soft Gelatin Capsules
What are higher ratios of dry plasticizer to dry gelatin used for?
water-miscible vehicles
Soft Gelatin Capsule Shells
What is the typical residual shell water content?
6-10%
Soft Gelatin Capsule Shells
Other than gelatin (and addition of glycerin/glycerol or sorbitol), what are other components of the shell?
- dyes
- opacifiers
- preservatives
- flavours
Soft Gelatin Capsule Formulation
What is it useful for formulating?
oil (most frequently) or other liquid substances that cannot easily be incorporated into powders
Soft Gelatin Capsule Formulation
What might soft gelatin capsules contain?
- single liquid
- combination of miscible liquids
- solution of a drug in a liquid or a suspension of a drug in a liquid
Soft Gelatin Capsule Formulation
What are liquids in soft gelatin capsules limited to?
liquids are limited to those that do not have an adverse effect on the gelatin walls (2.5 < pH < 7.5)
- aqueous liquids (> 5% water content) cannot be filled
- in general, all liquids used for filling must flow by gravity at a temperature of 35ºC
Soft Gelatin Capsule Formulation
What is the sealing temperature of gelatin film?
37ºC
Soft Gelatin Capsule Formulation
Examples
- long-chain and medium-chain triglyceride (vegetable oils) as a vehicle for highly lipophilic compounds
- water insoluble vitamins
- low volume liquid formulations (such as PEG 400, PEG 600) that accelerate dissolution of drugs
What is EPANOVA?
(SEE NOTES)
- lipid-regulating agent
- coated soft-gelatin capsule containing 1 gram of fish oil-derived free fatty acids
What are the compatibility and stability concerns for soft gelatin capsules?
there is more intimate contact between the shell and its liquid content, which increases the possibility of interactions
- number of excipients used in soft-gelatin capsules (plasticizers, PEGs) are known to undergo auto-oxidation to form higher molecular weight aldehydes, which can lead to loss of gelatin aqueous solubility by crosslinking
- drugs can migrate from oily vehicle to the shell
- hygroscopic compounds may attract water, taking it from the gelatin shell
- emulsions may release water to the gelatin shell
What is marinol?
(SEE SLIDES)
What is tetrahydrocannabinol (THC)?
active ingredient in marijuana that is a highly hydrophobic compound (BCS II) with extremely low bioavailability when administered orally
- has been shown to improve appetite and to reduce nausea in terminal-stage AIDS and cancer patients
- solubilized in sesame oil (long-chain triglycerides) which is packed into soft gelatin capsule
Soft Gelatin Capsule Filling
What is the rotary die process?
- liquid gelatin flowing from an overhead tank is formed into 2 continuous ribbons by the rotary die machine
- gelatin ribbons are brought into convergence between the twin revolving dies and an injection wedge which injects the filling material
- the fill material is injected between the ribbons at the moment that the twin dies form pockets in the gelatin ribbons
- capsules are sealed by pressure and heat
- the machine ejects the completed capsule
- the pumps are engineered to extremely high degree of precision and accuracy
- markings may be applied
- waste gelatin is recycled
Soft Gelatin Capsule Filling
What does the rotary die process allow encapsulation of?
heavy materials, such as ointments and pastes
Standard Softgel Machine
(see slides)
What are the advantages of soft gelatin capsules? (7)
- smooth and easy to swallow
- tasteless (good for taste masking)
- complete sealing (for oxygen sensitive materials)
- high accuracy and precision possible (important especially for highly potent compounds – better than hard gelation capsules)
- for some poorly water-soluble drugs, may improve bioavailability (ie. in oils)
- reduced dustiness, no compression stage in the manufacturing
- can make specialty shapes (round, oval, suppository)
What are the limitations of soft gelatin capsules? (3)
- stability issue due to more contact between shell and contents – investigate interactions during formulation and stability testing
- not appropriate for more than one kind of fill in the same capsule
- usually more expensive to produce than hard capsules or tablets – limited number of specialty manufacturers, and problematic if even one gelatin capsule breaks during preparation because it likely contaminates nearby capsules
Hard Capsules vs. Soft Capsules
Shell
- hard: not plasticized
- soft: plasticized – glycerin, sorbitol
Hard Capsules vs. Soft Capsules
Manufacturing Process
- hard: shells and filling are separate steps
- soft: one step
Hard Capsules vs. Soft Capsules
Content
- hard: usually dry solids
- soft: usually liquids/suspensions
Hard Capsules vs. Soft Capsules
Fill Accuracy
- hard: 2-5% (automated)
- soft: 1-3%
Hard Capsules vs. Soft Capsules
Size and Shape
- hard: limited
- soft: many
Hard Capsules vs. Soft Capsules
Closure
- hard: friction, mechanical lock, banding, liquid sealing
- soft: hermetically sealed (heat)
Describe capsule (both hard and soft) quality control.
(like with tablets)
- disintegration
- dissolution
- weight variation (between 90-110%)
- content uniformity (between 85-115% of label)
- stability
- moisture permeation
Better Bioavailability of Soft Gelatin Capsules
in soft gelatin capsules, we can ‘package’ the drug together with solvents (ie. alcohol) and oils that are not possible with tablets or hard gelatin capsules
- therefore the potential (and proven) better bioavailability comes from those excipients
